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Showing posts with label Bipolar. Show all posts
Showing posts with label Bipolar. Show all posts

Thursday, 26 September 2019

Treatable Human Endogenous Retroviruses (HERVs) in Multiple Sclerosis (MS), ALS and other Neurological Diseases – an Enemy from Within?



  
A microglial cell, labelled in green, contacts and attacks a myelinated axon (in red). In the presence of the pHERV-W envelope protein, this interaction leads to axonal injury. The blue structures are cell nuclei. Credit: HHU / Joel Gruchot / Patrick Küry
  

It is surprising that only about 2% of human DNA encodes the 20,000 or so genes we all have.  The other 98% used to be called junk DNA.

About 8% of your DNA is made up of Endogenous retroviruses (ERVs) that have been picked up during evolution and most of which have been inactivated and can indeed be regarded as junk. Some of these old viruses that became part of human DNA remain fully functional, can be activated; they are implicated in disease ranging from Multiple Sclerosis (MS), to cancer, to schizophrenia and ALS (motor neuron disease).

The best documented ERV is the one that affects some people with MS, it is called HERV-W  (the H is for Human).  Only in the presence of a protein encoded by this virus can the microglia cells attack the myelin layer on axons.  In this kind of MS, if you could switch off the HERV-W virus you would solve the remyelination problem.

The thing to remember is that MS is a family of conditions and HERV-W may only be relevant to specific sub-types.  The recent research (see below) produced the image at the start of today’s post, where we actually see the microglia (green) mistakenly attacking the healthy myelin on axons (red).

Multiple sclerosis: Endogenous retrovirus HERV-W key to nerve tissue damage


As outlined by first author Dr. David Kremer, the envelope (ENV) protein of the pathogenic human endogenous retrovirus type W (pHERV-W) was found to be a major contributor to nerve damage in MS. In collaboration with research teams in the U.S. and Canada, the authors demonstrated that the ENV protein drives CNS resident microglial cells to contact and damage myelinated axons.                                                                                      



There is a broad repertoire of immunomodulatory drugs that effectively treat the inflammatory aspects of relapsing multiple sclerosis (MS). However, axonal degeneration, which occurs mainly in progressive MS, is still not understood and cannot be treated pharmaceutically. As it is the major factor contributing to clinical disability in MS, it represents an unmet clinical need. A recently completed phase IIb study has demonstrated that anti-pathogenic human endogenous retrovirus type W (pHERV-W) envelope protein (ENV) treatment results in a significant decrease of neurodegenerative brain atrophy in treated MS patients. For these results, the work presented here offers an explanation by demonstrating that, via myeloid cells, pHERV-W ENV directly harms axons.

Axonal degeneration is central to clinical disability and disease progression in multiple sclerosis (MS). Myeloid cells such as brain-resident microglia and blood-borne monocytes are thought to be critically involved in this degenerative process. However, the exact underlying mechanisms have still not been clarified. We have previously demonstrated that human endogenous retrovirus type W (HERV-W) negatively affects oligodendroglial precursor cell (OPC) differentiation and remyelination via its envelope protein pathogenic HERV-W (pHERV-W) ENV (formerly MS-associated retrovirus [MSRV]-ENV). In this current study, we investigated whether pHERV-W ENV also plays a role in axonal injury in MS. We found that in MS lesions, pHERV-W ENV is present in myeloid cells associated with axons. Focusing on progressive disease stages, we could then demonstrate that pHERV-W ENV induces a degenerative phenotype in microglial cells, driving them toward a close spatial association with myelinated axons. Moreover, in pHERV-W ENV-stimulated myelinated cocultures, microglia were found to structurally damage myelinated axons. Taken together, our data suggest that pHERV-W ENV-mediated microglial polarization contributes to neurodegeneration in MS. Thus, this analysis provides a neurobiological rationale for a recently completed clinical study in MS patients showing that antibody-mediated neutralization of pHERV-W ENV exerts neuroprotective effects.


Relapsing-Remitting Multiple Sclerosis (RRMS)

Most MS starts out as so-called Relapsing-Remitting Multiple Sclerosis (RRMS) and so is the focus of much research. An antibody called GNbAC1 has been developed to specifically target the protein MSRV-Env that is produced by the old human endogenous retrovirus type W.

GNbAC1 for RRMS 

In vitro and in vivo studies showed that GNbAC1 neutralizes MSRV-Env, reducing the inflammatory response and allowing the remyelination repair process to restart.

I think this is an excellent example of how to translate complicated science into a practical therapy.  I just hate to think how much money this therapy will cost.


Or just Antivirals?

I did wonder about a less expensive therapy to block the MSRV-Env protein from activating microglia to destroy myelin.  Why not use a relatively cheap antiviral drug to dampen the virus itself, so it does not make the harmful protein?

Unlike most antibiotics, antiviral drugs do not destroy their target pathogen; instead they inhibit their development.

Antiviral drugs normally have to be developed to target a specific virus, but you might just get lucky with an existing drug.

In the case of HIV, a combination of three drugs is used TDF (tenofovir), EFV (efavirenz) and either 3TC (lamivudine) or FTC (emtricitabine).  This therapy has been hugely successful.

The anti-herpes antivirals include valacyclovir (Valtrex), famciclovir (Famvir), and acyclovir (Zovirax).

In the case of Multiple Sclerosis, I did find a study that used acyclovir.  It did not cure the condition, but it did significantly reduce exacerbations.
                                                       






I am afraid nobody seems to want a cheap drug for MS, when the other only partially effective ones can cost $50,000 a year. Acyclovir is much more expensive in the US than elsewhere but nothing like the price of the new MS drugs.

It may of course be a coincidence that Acyclovir reduces exacerbations in MS and may involve an entirely different mechanism.


Human endogenous retroviruses (HERVs) beyond MS

Drugs for MS are a huge business for pharmaceutical companies and this is why the research is advanced.

HERVs have been implicated in ALS (motor neuron disease) and schizophrenia.  There is even some research on HERVs and autism.

It is usually the Herpes virus that gets mentioned in the context of autism. It is probably one of hundreds of possible triggers that, when combined with other “hits” and genetic predispositions, may lead to autism.

Any virus can affect gene expression and so any virus has the potential to cause harm to a developing brain.  This is often all "autism" is, the result of some damage at a critical point in the brain's development. That same event in a teenager does no long term harm. 


Herpes virus may be a trigger for autism

“We’re not saying that HSV-2 is responsible for infecting the [fetal] brain and causing autism,” stresses senior author Ian Lipkin, an infectious disease expert and epidemiologist at Columbia. Indeed, fetal infection with HSV-2 is so serious that it frequently leads to miscarriages or stillbirths. Rather, Lipkin suspects that HSV-2 is just one among many environmental insults that, when they arrive at a vulnerable point in fetal development in women predisposed to damaging reactions, may trigger ASD in the fetus. That idea comports with a body of previous work, like this Swedish study that found that the hospitalization of a woman for any kind of infection during pregnancy increased the risk of the baby developing ASD by 30%.
Some scientists are skeptical that inflammatory molecules alone could be responsible, in part because of the big changes in brain structure that arise in autistic children in the first 2 years of life, just as symptoms of ASD emerge. For instance, a study published in Nature last week documents abnormal overgrowth of the surface of the brain in 6- to 12-month-old babies who go on to be diagnosed with ASD.

Are the 'viral' agents of MS, ALS and schizophrenia buried in our genome?

Viruses hid themselves in your ancestors' DNA; now they're waking up


What if the missing 'environmental' factor in some of our deadliest neurological diseases were really written in our genome? Researchers explain how viruses ended up in our DNA -- and what puts them in the frame in unsolved diseases like multiple sclerosis.

The enemy within
A whopping 8% of our DNA comes from viruses. Specifically, ones called retroviruses -- not because they're old, but because they reverse the normal process of reading DNA to write themselves into their host's genome.
Retroviruses are old though: they began merging with our earliest, primordial ancestors millions of years ago. Over the millennia, most of their remnants in our DNA -- known as human endogenous retroviruses or HERVs -- have been silenced by mutations. Others, which had evolved to fend off rival viruses, formed the prototypical immune system and to this day protect us from infection.
However, HERVs might also be the missing causative link in major 'unsolved' neurological diseases.
"HERVs have been implicated in the onset and progression of multiple sclerosis [MS], amyotrophic lateral sclerosis [ALS] and schizophrenia [SCZ]," says senior author Prof. Patrick Kuery. "Dormant HERVs can be reactivated by environmental factors such as inflammation, mutations, drugs, or infection with other viruses, so could provide a mechanism for their well-established epidemiological link to these disorders."

Full paper: -

Neural Cell Responses Upon Exposure to Human Endogenous Retroviruses

Human endogenous retroviruses (HERVs) are ancient retroviral elements, which invaded the human germ line several million years ago. Subsequent retrotransposition events amplified these sequences, resulting in approximately 8% of the human genome being composed of HERV sequences today. These genetic elements, normally dormant within human genomes, can be (re)-activated by environmental factors such as infections with other viruses, leading to the expression of viral proteins and, in some instances, even to viral particle production. Several studies have shown that the expression of these retroviral elements correlates with the onset and progression of neurological diseases such as multiple sclerosis (MS) and amyotrophic lateral sclerosis (ALS). Further studies provided evidence on additional roles for HERVs in schizophrenia (SCZ). Since these diseases are still not well understood, HERVs might constitute a new category of pathogenic components that could significantly change our understanding of these pathologies. Moreover, knowledge about their mode of action might also help to develop novel and more powerful approaches for the treatment of these complex diseases. Therefore, the main scope of this review is a description of the current knowledge on the involvement of HERV-W and HERV-K in neurological disease specifically focusing on the effects they exert on neural cells of the central nervous system.

Importantly, several studies were able to show that inflammation plays a major role in HERV activation 

SCZ is a complex neuropsychiatric disorder characterized by a variety of cognitive, emotional, and perceptual disturbances. Pathophysiologically, SCZ features decreased brain volume, loss of myelin, and altered astrocyte function (Archer, 2010). In contrast to MS and ALS, both HERV-W and HERV-K have been weakly linked to SCZ based on PCR amplification from CSF and post-mortem brains as well as on protein antigenemia (Yolken et al., 2000Karlsson et al., 2001Frank et al., 2005Perron et al., 2008), while another study revealed upregulation of HERV-W ENV transcripts in plasma samples of SCZ patients (Huang et al., 2011). Moreover, a new study provides evidence that, in early stages of this disease, HERV-K methylation in peripheral blood is reduced (Mak et al., 2019). Of note, these observations contradict an earlier report suggesting that HERV-W expression is reduced in SCZ patients (Weis et al., 2007). The disparity between these reports may reflect different experimental approaches or a differential use of anti-psychotic medications in SCZ patients.

We here present collected evidence that endogenous retroviral elements acting either as viral particles or via their proteins influence neural cells in the context of degenerative CNS diseases. Once thought to be primarily involved in cell transformation (Grabski et al., 2019) and inflammation (Perron and Lang, 2010), emerging data suggests a direct role of these elements in glial and neuronal injury, which in fact goes beyond previous descriptions on the activity of a gliotoxin (Menard et al., 1998). In light of additional observations on the role of ERVs in regulating stem cell potential and fate acquisition (Gautam et al., 2017), the findings describing impacts on committed or mature cells of the CNS are probably not too surprising but warrant future investigations, even more so since neural stem cells are also involved in brain pathology and regeneration. Moreover, the currently still unmet clinical need to effectively treat neurodegeneration necessitates novel therapeutic approaches. Whether similar mechanisms also apply to activation of transposable elements implicated in, for example, chronic fatigue syndrome (CFS; Almenar-Perez et al., 2019) and to what degree currently used neutralizing antibodies can be exploited in order to prevent neural cell activation and/or neurodegeneration needs to be elucidated in the future. In this regard, it remains to be shown whether HERV-employed signaling pathways and epigenetic silencing mechanisms can be used for biomedical translation.



                        

Figure 1 HERV-mediated effects on neural cells. This illustration summarizes origin and observed molecular effects of HERW-W and HERV-K on cells of the central nervous system. Arrow starting points indicate cellular sources of HERV particles or proteins (red dots), whereas arrowheads point to influenced cell types. Modulated processes are shown in gray boxes, and regulated molecules are highlighted in red next to each cell type. The question mark next to TDP-43 refers to its postulated regulation in neurons. Whether microglia and astroglia respond to HERVs in an auto- and/or paracrine way and whether neurons react to internal and/or extracellular HERVs remains to be shown. OPCs: oligodendroglial progenitor cells; NO: nitric oxide; CRP: C-reactive protein; BDNF: brain-derived neurotrophic factor; DRD3: dopamine receptor D3; TRPC3: short transient receptor potential channel 3; DISC1: disrupted in schizophrenia 1; TDP-43: TAR DNA-binding protein 43.
                                  

HERVs, retroviral sequences integrated into the genome during evolution, are now known to represent 8% of the human genome.






These were recently shown to comprise copies that retain potential to express retroviral proteins or particles, and can be abnormally expressed in autoimmune, neurodegenerative, chronic inflammatory diseases, and cancer.
Environmental factors such as specific viral infections were shown to potently activate HERVs under tissue-specific and temporal conditions.
Of several diseases in which abnormal activation and expression of HERV proteins have been reported, studies over recent decades have led to a proof of concept that HERVs play a key role in the pathogenesis of MS and ALS.
HERV-W and HERV-K Env proteins induce pathogenic effects in vitro and in vivo that are relevant to the pathognomonic features of these diseases.
These endogenous retroviruses are potential novel therapeutic targets that are now being addressed with innovative therapeutic strategies in clinical trials.
The causes of multiple sclerosis and amyotrophic lateral sclerosis have long remained elusive. A new category of pathogenic components, normally dormant within human genomes, has been identified: human endogenous retroviruses (HERVs). These represent ∼8% of the human genome, and environmental factors have reproducibly been shown to trigger their expression. The resulting production of envelope (Env) proteins from HERV-W and HERV-K appears to engage pathophysiological pathways leading to the pathognomonic features of MS and ALS, respectively. Pathogenic HERV elements may thus provide a missing link in understanding these complex diseases. Moreover, their neutralization may represent a promising strategy to establish novel and more powerful therapeutic approaches.

HERVs Expression in Autism Spectrum Disorders

Results

The percentage of HERV-H and HERV-W positive samples was higher among ASD patients compared to HCs, while HERV-K was similarly represented and HERV-E virtually absent in both groups. The quantitative evaluation shows that HERV-H and HERV-W are differentially expressed in the two groups, with HERV-H being more abundantly expressed and, conversely, HERV-W, having lower abundance, in PBMCs from ASDs compared to healthy controls. PMBCs from ASDs also showed an increased potential to up-regulate HERV-H expression upon stimulation in culture, unlike HCs. Furthermore we report a negative correlation between expression levels of HERV-H and age among ASD patients and a statistically significant higher expression in ASD patients with Severe score in Communication and Motor Psychoeducational Profile-3.

Conclusions

Specific HERV families have a distinctive expression profile in ASD patients compared to HCs. We propose that HERV-H expression be explored in larger samples of individuals with autism spectrum in order to determine its utility as a novel biological trait of this complex disorder.



Recent studies suggest that autism spectrum disorders (ASD) result from interactions between genetic and environmental factors, whose possible links could be represented by epigenetic mechanisms. Here, we investigated the transcriptional activity of three human endogenous retrovirus (HERV) families, in peripheral blood mononuclear cells (PBMCs) from Albanian ASD children, by quantitative real-time PCR. We aimed to confirm the different expression profile already found in Italian ASD children, and to highlight any social and family health condition emerging from information gathered through a questionnaire, to be included among environmental risk factors. The presence of increased HERV-H transcriptional activity in all autistic patients could be understood as a constant epigenetic imprinting of the disease, potentially useful for early diagnosis and for the development of effective novel therapeutic strategies.

Overall, the data obtained in the present study lead us to further support the hypothesis that HERV transcriptional activity is influenced by all the factors mentioned above. Additional work is required to determine if HERV-H expression could be proposed as a biological marker, useful for early detection of children at high risk for ASD, before the appearance of clinical symptoms and for the development of effective new therapeutic strategies. To this end, an in-depth characterization of the potential role of HERV-H in ASD is the major objective of a study currently in progress in murine models. Currently, up to 2% of children worldwide are estimated to be diagnosed with an ASD (Pedersen et al., 2014) and the consistent increment in the prevalence of ASD is considered a pressing challenge for the global public health system. Because children represent more than a third of the Albanian population (Albanian Institute of Statistics 2011) autism is a serious socio-economic problem and its early diagnosis could represent a significant improvement in the treatment of the disease. In fact, if the autistic condition is diagnosed early, a growing repertoire of evidence-based therapies can be applied to give children the best possible chance of life.


Etiotropic and Pathogenetic Therapy of Autism Spectrum Disorder: Case Series of 6 Children


Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder that reveals itself by social communication problems, restrictive/repetitive behavior, and language impairment. ASD is a growing problem in the USA and in the world with no commonly-accepted etiology resulting in the absence of effective methods of treatment. Based on more than 80 scientific publications we are proposing the following understanding of ASD: it is a genetic disorder, in which some changes in DNA are resulting from a congenital mother to fetus transmitted infection and maternal immune activation. The infections and maternal immune activation result in oxidative stress and production of pro-inflammatory cytokines and other mediators. Based on this understanding, we developed a method of long-term etiotropic and pathogenetic therapy tailored to major chronic/latent infections, inflammation and immune system aberration. We present six cases of ASD treatment, which included the antiviral medication Valacyclovir and five nutritional supplements. The presented results are based on five cycles of treatment continued for 5 months. In all six cases the treatment resulted in social communication skills and behavioral improvements well as positive changes in the physical and psychological conditions. These improvements covariated with a tendency to normalization of blood and immune parameters. Social communication skills, behavioral, physical and psychological improvements also positively affected parents whose subjected quality of life increased over course of the treatment. According to parents of these children, the proposed treatment had superior efficacy compared to other types of treatment that their children underwent before.


Valacyclovir improves cognition in bipolar patients


A 4-month course of the oral antiviral agent valacyclovir boosted cognition in herpes simplex virus-1–seropositive patients with bipolar disorder and cognitive impairment in a randomized, double-blind placebo-controlled clinical trial.

Anti herpes Virus–Specific Treatment and Cognition in Schizophrenia: A Test-of-Concept Randomized Double-Blind Placebo-Controlled Trial

Objective

To test our hypothesis that valacyclovir, an antiherpes virus–specific medication, added to antipsychotics (APs) would improve cognitive performance and psychopathology among schizophrenia subjects exposed to neurotropic herpes simplex virus, type 1 (HSV1).

Methods

Using a double-blind placebo-controlled design, we randomized 24 HSV1-seropositive schizophrenia subjects to receive either valacyclovir (n = 12) or placebo (n = 12) for 18 weeks in addition to stable doses of APs. Valacyclovir dose was stabilized at 1.5 g twice daily orally. At each visit, subjects were evaluated for severity of psychopathology and side effects using standardized scales and a study-specific semistructured checklist. A computerized neurocognitive battery validated on both schizophrenia and healthy subjects was administered at baseline and follow-up. Intent-to-treat analysis, using linear regression models that included all randomized subjects, were used to examine differential changes in cognition and psychopathology scores over 18 weeks between valacyclovir and placebo, accounting for placebo response.

Results

Valacyclovir group improved in verbal memory, working memory, and visual object learning compared with placebo group. The effect sizes (Cohen’s d) were 0.79 for working memory, 1.14 for immediate verbal memory, and 0.97 for the visual object learning. Psychotic symptom severity did not improve.

Conclusions

Supplemental valacyclovir may alleviate impairments in cognitive domains that are often observed in schizophrenia but not psychotic symptoms in those exposed to HSV1. If replicated, this approach could provide a novel strategy to treat cognitive impairments in a subgroup of schizophrenia subjects who can be reliably identified using a blood test.


Conclusion

There is a great deal going on in the world of MS research and if you have MS you might as well consider becoming an early adopter.

As expected, the research on how these old viruses, that should be dormant in our DNA, might play a role in autism is not very advanced.

Some people with autism do take antiviral drugs and I think their caregivers think this relates to a virus they have acquired recently or comes from the mother. Perhaps it is an unidentified virus from that 8% of your DNA that has become activated?

In MS the story is complex but now we know for sure what the virus is, where it came from and what it does. You can defeat it with a tailor-made antibody called GNbAC1 or perhaps just beat it down a little with the common antiviral drug Acyclovir.

Note that antiviral drugs each only have an effect on certain types of virus.

Do HERVs really materially affect some people with autism, and its big brothers bipolar and schizophrenia? There is some limited evidence that they may.

People who report that their children with autism do indeed improve on an antiviral drug are unlikely to ever know which virus was the problem and it may not be the one they thought it was, but it is not a crazy idea.  If it reduces the symptoms of autism without causing troubling side effects, why not?  It is going to work for most autism? Probably not.

For people with Multiple Sclerosis (MS) the science is clear and unambiguous, you need to wipe out the protein called MSRV-Env.

As far as this blog is concerned, we already covered antibiotics in depth.


and today we covered antivirals.  These are the “anti- drugs” that our reader Tanya referred to as not being useful in her case of autism; I think she will be in the majority.  You have to treat your “minority” case of autism, which is what makes it difficult. 

Almost every common autism treatment strategy is misrepresented as a wonder therapy; that is how you sell books, supplements, lab tests and even now I see expensive "training" courses. The reality is somewhat messy and less convenient, but if you read the science great progress does seem to be possible in many cases.






Thursday, 24 January 2019

Cheap common drugs may help mental illness










Stockholm, Sweden

When most people think of Sweden, they probably think of Volvo cars, now actually Chinese, and Ikea.  Today you will have to add keeping detailed centralized medical records to the list.
Today’s study included 142,691 individuals from the entire population of Sweden with a diagnosis of bipolar disorder (BPD), schizophrenia (SCZ), or nonaffective psychosis (NAP) who were 15 years or older and who were treated with psychiatric medication from October 1, 2005, through December 31, 2016. 
It is relevant to readers of this blog because it shows that some of the same cheap generic drugs written about in this blog to modify aspects of autistic brain function do indeed show up as beneficial to those Swedes, with BPP, SCZ or NAP, who had by chance been prescribed those drugs for other reasons.
Numerous genetic studies have shown that the genes miss-expressed in autism overlap with those miss-expressed in bipolar (BPD) and schizophrenia (SCZ).
Clearly some people will get upset about autism (AUT) being called a mental illness. Whatever you choose to call SCZ and BPD you really need to apply to AUT, they are clearly just 3 overlapping clusters of gene miss-expression.
The study was summed up nicely in this BBC article.


Cheap and widely used drugs for diabetes and heart health have potential for treating severe mental illness, a study hints.
It showed the number of times patients needed hospital treatment fell by up to a fifth when they took the drugs.
The researchers at University College London say their findings have "enormous potential".
But they, and independent experts, say the results now need to be tested in clinical trials.
The starting point for the researchers was a list of currently prescribed medications that science predicts could also help patients with severe mental health disorders.
The team focused on:
§  anti-cholesterol drugs called statins - which may calm inflammation linked to mental health problems or help the body absorb anti-psychotic medications
§  blood pressure drugs - which may alter the calcium signalling in the brain that has been linked to bipolar disorder and schizophrenia
§  type 2 diabetes drug metformin - which may alter mood
But rather than test them in trials, the scientists went looking for evidence in the real world.
   
The press release from the lead author, who is at University College London



The full paper



Key Points

Question  Are drugs in common use for physical health problems (hydroxylmethyl glutaryl coenzyme A reductase inhibitors, L-type calcium channel antagonists, and biguanides) associated with reduced rates of psychiatric hospitalization and self-harm in individuals with serious mental illness?
Findings  In this series of within-individual cohort studies of 142 691 patients with bipolar disorder, schizophrenia, or nonaffective psychosis, exposure to any of the study drugs was associated with reduced rates of psychiatric hospitalizaiton compared with unexposed periods. Self-harm was reduced in patients with bipolar disorder and schizophrenia during exposure to all study drugs and in patients with nonaffective psychosis taking L-type calcium channel antagonists.
Meaning  Hydroxylmethyl glutaryl coenzyme A reductase inhibitors, L-type calcium channel antagonists, and biguanides hold potential as repurposed agents in serious mental illness, and the central nervous system mechanism of action of these drugs requires further investigation.
Abstract 
Importance  Drug repurposing is potentially cost-effective, low risk, and necessary in psychiatric drug development. The availability of large, routine data sets provides the opportunity to evaluate the potential for currently used medication to benefit people with serious mental illness (SMI).
Objective  To determine whether hydroxylmethyl glutaryl coenzyme A reductase inhibitors (HMG-CoA RIs), L-type calcium channel (LTCC) antagonists, and biguanides are associated with reduced psychiatric hospitalization and self-harm in individuals with SMI.
Design, Setting, and Participants  These within-individual cohort studies of patients with SMI compared rates of psychiatric hospitalization and self-harm during periods of exposure and nonexposure to the study drugs, with adjusting for a number of time-varying covariates. Participants included 142 691 individuals from the entire population of Sweden with a diagnosis of bipolar disorder (BPD), schizophrenia, or nonaffective psychosis (NAP) who were 15 years or older and who were treated with psychiatric medication from October 1, 2005, through December 31, 2016. Data were analyzed from April 1 through August 31, 2018.
Interventions  Treatment with HMG-CoA RIs, LTCC antagonists, or biguanides.
Main Outcomes and Measures  Psychiatric hospitalizations and self-harm admissions.
Results  Among the 142 691 eligible participants, the HMG-CoA RI exposure periods were associated with reduced rates of psychiatric hospitalization in BPD (adjusted hazard ratio [aHR], 0.86; 95% CI, 0.83-0.89; P < .001), schizophrenia (aHR, 0.75; 95% CI, 0.71-0.79; P < .001), and NAP (aHR, 0.80; 95% CI, 0.75-0.85; P < .001) and reduced self-harm rates in BPD (aHR, 0.76; 95% CI, 0.66-0.86; P < .001) and schizophrenia (aHR, 0.58; 95% CI, 0.45-0.74; P < .001). Exposure to LTCC antagonists was associated with reduced rates of psychiatric hospitalization and self-harm in subgroups with BPD (aHRs, 0.92 [95% CI, 0.88-0.96; P < .001] and 0.81 [95% CI, 0.68-0.95; P = .01], respectively), schizophrenia (aHRs, 0.80 [95% CI, 0.74-0.85; P < .001] and 0.30 [95% CI, 0.18-0.48; P < .001], respectively), and NAP (aHRs, 0.89 [95% CI, 0.83-0.96; P = .002] and 0.56 [95% CI, 0.42-0.74; P < .001], respectively). During biguanide exposure, psychiatric hospitalization rates were reduced in subgroups with BPD (aHR, 0.80; 95% CI, 0.77-0.84; P < .001), schizophrenia (aHR, 0.73; 95% CI, 0.69-0.77; P < .001), and NAP (aHR, 0.85; 95% CI, 0.79-0.92; P < .001), and self-harm was reduced in BPD (aHR, 0.73; 95% CI, 0.62-0.84; P < .001) and schizophrenia (aHR, 0.64; 95% CI, 0.48-0.85; P < .001.
Conclusions and Relevance  This study provides additional evidence that exposure to HMG-CoA RIs, LTCC antagonists, and biguanides might lead to improved outcomes for individuals with SMI. Given the well-known adverse event profiles of these agents, they should be further investigated as repurposed agents for psychiatric symptoms.

Conclusion
If you are trying to convince your GP to prescribe some drugs off-label for autism, this study may help you convince him/her.
If your spouse, or other family members, think treating autism is folly, they might also benefit from reading about this study. 

The very old drug Metformin, used to treat type 2 diabetes has been mentioned many times in this blog and in today's study it was suggested to alter mood.  For severe autism mood is often not such a big issue, but for some mild autism mood is the big issue.
This study again shows how Scandinavian medicine collects a great deal of very usable data, in a recent post we saw something similar from Denmark. This is an example of socialized medicine at its best. I suppose the English lead author could not gather equivalent data in his home country.






Monday, 11 December 2017

Cognitive Loss/Impaired Sensory Gating from HCN Channels - Recovered by PDE4 Inhibition or an α2A Receptor Agonist

Today we have a complex dysfunction, but we have a plausible understanding of the detailed biological underpinnings and several therapeutic options. It is relevant to people with autism who have impaired sensory gating (they find noises like a clock ticking annoying), and perhaps those who struggle with complex thought. It is very likely to be disturbed in some people with ADHD and many with schizophrenia.

Trouble in the Pre-Frontal Cortex


For a recap on sensory gating, here is an earlier post:-

Sensory Gating in Autism, Particularly Asperger's


Today’s dysfunction relates to HCN channels located on those tiny dendritic spines in a part of the brain called the pre-frontal cortex. These are a type of voltage gated potassium channel found in your brain and heart, there are 4 types, it looks to me that HCN2 is the key one today.
The pre-frontal cortex (PFC) is seen as the part of the brain most affected by mental illness (schizophrenia, bipolar, ADHD etc.), although medicine’s current understanding looks rather medieval to me.
These HCN channels can open when they are exposed to cAMP (cyclic adenosine monophosphate). When open, the information can no longer flow into the cell, and thus the network (created by numerous interacting neurons) is effectively disconnected.
By keeping these channels closed, it is thought that you can improve working memory and reducing distractibility. Now you might think distractibility is an odd word, and it is not a word I expected to encounter, what it really means is impaired sensory gating. This is a core feature of Asperger’s, ADHD and schizophrenia.
One of the key risk genes for schizophrenia, DISC1, also affects HCN channels and this may account for some of the cognitive deficit found in schizophrenia. High level thinking is particularly affected.  It is thought that loss of DISC1 function in the PFC would likely prevent proper PDE4 function, leading to a dysregulated build-up of cAMP in dendritic spines resulting in excessive opening of HCN channels


I did wonder how nicotine fits in, since in earlier post we saw that α7 nAChR agonists, like nicotine, improve sensory gating and indeed that people with schizophrenia tend to be smokers. It turns out that nicotine is also an HCN channel blocker. For a change, everything seems to fit nicely together. There are different ways to block HCN channels, some of which are indirect. One common ADHD drug, Guanfacine, keeps these channels closed, but in a surprising way.
Alpha-2A adrenergic receptors near the HCN channels, on those dendritic spines, inhibit the production of cAMP and the HCN channels stay closed, allowing the information to pass through into the cell, connecting the network. These Alpha-2A adrenergic  receptors are stimulated by a natural brain chemical norepinephrine, or by drugs like Guanfacine.
Stress appears to flood PFC neurons with cAMP, which opens HCN channels, temporarily disconnects networks, and impairs higher cognitive abilities.
This would explain why stress makes people’s sensory gating problems get worse. So someone with Asperger’s would get more distracted/disturbed at exam time at school for example, or when he goes for a job interview. Reducing stress is another method to improve sensory gating and indeed cognition. In Monty, aged 14 with ASD, the only time he exhibits significantly impaired sensory gating, is when he has stopped all his Polypill therapies for several days. I think stress/anxiety is what has changed and this opens those HCN channels. Then even the sound of someone eating food next to him makes him angry.
Excessive opening of HCN channels might underlie many lapses in higher cognitive function.
While the researchers at Yale patented the idea of HCN blockers to improve cognition, we can see how other existing ideas to improve cognition may indeed have the same mechanism, most notably PDE4 inhibitors.
The University of Maastricht holds patents on the use of Roflumilast, a PDE4 inhibitor, to improve cognition; most interestingly, this takes effect at one fifth of the COPD dosage, for which it is an approved drug. At high doses PDE4 inhibitors have annoying side effects, but at low doses they tend to be trouble-free.
One effect of a PDE4 inhibitor is that it reduces cAMP. So a PDE4 inhibitor acts indirectly like an HCN blocker.
Not surprisingly recent research showed that low doses of Roflumilast improves sensory gating in those affected by this issue.
So rather than waiting for a brain selective HCN blocker, the potential exists to use a one fifth dose of Roflumilast today. This is something that should indeed be investigated across different types of cognitive dysfunction.
There are numerous dysfunctions that can impair cognition and they can occur in different diagnosis. For example impaired autophagy is a key feature of Huntington’s, impaired remyelination defines multiple sclerosis, low levels of nerve growth factor are a key feature of Rett syndrome. Less severe dysfunctions of these processes occur in entirely different conditions.
It is thought that people with Alzheimer’s might benefit from PDE4 inhibition. If it was me, I would try it in all types of dementia or cognitive loss of any kind.

PDE4 Inhibitors
There have been many mentions of PDE4 inhibitors elsewhere in this blog. They are broadly anti-inflammatory and anti-oxidant, but currently only widely used to treat asthma in Japan and COPD in Western countries. COPD is a kind of very severe asthma.
Traditionally a PDE4 inhibitor is thought of as drug used to block the degradative action of phosphodiesterase 4 (PDE4) on cyclic adenosine monophosphate (cAMP). That all sound complicated, just think of it as increasing cAMP.
Now cAMP is a messenger in many biological processes, one of which relates to PKA (Protein Kinase A). In autism we know that PKA, PKB and PKC are often disturbed. These PKs are very important because they have the ability to literally change the function of thousands of proteins in your body. This is similar to how epigenetic tags can switch on or switch off a particular gene. PKs, via a different mechanism we will look at in another post, change the function of proteins, so it is very important that you have the correct level of PKA, PKB and PKC.
We saw in a recent post that the Pitt Hopkins gene TCF4 is regulated by PKA and that under-expression of TCF4 is also a feature of some ID and schizophrenia. So more PKA, please.

You can use a PDE4 inhibitor to increase cAMP, which then increases PKA.

Other effects of PDE4 inhibitors
Today’s post is about sensory gating and the effect here of PDE4 inhibitors is via the effect of cAMP on those HCN channels in your tiny dendritic spines.
There are numerous other effects of PDE4 that may also be therapeutic. One interesting effect is that inhibition of PDE4 can mimic calorie restriction by activating AMPK/SIRT1 pathway.
Calorie restriction has just been shown in a large trial to be able to reverse type 2 diabetes, if initiated with a few years of the disease developing.
Humans have evolved based to periods of feast and famine. Periods of fasting may be therapeutic for many modern conditions.
Not surprisingly one side effect of PDE4 inhibitors is weight loss. Many psychiatric drugs cause troubling weight gain.

Acute administration of Roflumilast enhances sensory gating in healthy young humans in a randomized trial. 

Abstract

 

INTRODUCTION:

Sensory gating is a process involved in early information processing which prevents overstimulation of higher cortical areas by filtering sensory information. Research has shown that the process of sensory gating is disrupted in patients suffering from clinical disorders including attention deficit hyper activity disorder, schizophrenia, and Alzheimer's disease. Phosphodiesterase (PDE) inhibitors have received an increased interest as a tool to improve cognitive performance in both animals and man, including sensory gating.

METHODS:

The current study investigated the effects of the PDE4 inhibitor Roflumilast in a sensory gating paradigm in 20 healthy young human volunteers (age range 18-30 years). We applied a placebo-controlled randomized cross-over design and tested three doses (100, 300, 1000 μg).

RESULTS:

Results show that Roflumilast improves sensory gating in healthy young human volunteers only at the 100-μg dose. The effective dose of 100 μg is five times lower than the clinically approved dose for the treatment of acute exacerbations in chronic obstructive pulmonary disease (COPD). No side-effects, such as nausea and emesis, were observed at this dose. This means Roflumilast shows a beneficial effect on gating at a dose that had no adverse effects reported following single-dose administration in the present study.

CONCLUSION:

The PDE4 inhibitor Roflumilast has a favourable side-effect profile at a cognitively effective dose and could be considered as a treatment in disorders affected by disrupted sensory gating.


Background Information
Selective phosphodiesterase (PDE) inhibition has been considered as a very promising target for cognition enhancement.
Roflumilast is a PDE4 inhibitor that has been developed by Takeda for Chronic Obstructive Pulmonary Disease (COPD). In recent year, Maastricht University has been collaborating with Takeda to develop Roflumilast for cognitive impairments
In 2015 Takeda sold COPD indication of Roflumilast to AstraZeneca, and ownership of IP for treatment of cognitive impairment returned to Maastricht University.
Compelling clinical results
A single administration of Roflumilast improves episodic memory in mice, and in young and elderly healthy subjects at a non-emetic dose
As shown in the figure, healthy (A) and memory impaired (B) elderly subjects showed better performances in the delayed recall of the Verbal Learning Task after roflumilast

Key Features and Advantages
Opportunities to reposition a clinically-proven safe compound with a well-established pharmacology.
Compelling preclinical and clinical evidences showing that Roflumilast effectively deliver to the brain to produce robust cognitive enhancement.
Pro-cognitive effects at low dose (5 times lower than COPD indication), which allows to circumvent the emetic effects commonly observed with other PDE4 inhibitors
Maastricht University has a strong IP protection extending to at least 2033.

PDE inhibitors in psychiatry--future options for dementia, depression and schizophrenia?

Author information

Abstract

Phosphodiesterases are key enzymes in cellular signalling pathways. They degrade cyclic nucleotides and their inhibition via specific inhibitors offers unique 'receptor-independent' opportunities to modify cellular function. An increasing number of in vitro and animal model studies point to innovative treatment options in neurology and psychiatry. This review critiques a selection of recent studies and developments with a focus on dementia/neuroprotection, depression and schizophrenia. Despite increased interest among the clinical neurosciences, there are still no approved PDE inhibitors for clinical use in neurology or psychiatry. Adverse effects are a major impediment for clinical approval. It is therefore necessary to search for more specific inhibitors at the level of different PDE sub-families and isoforms.


The current study found that brain cells in PFC contain ion channels called hyperpolarization-activated cyclic nucleotide-gated channels (HCN) that reside on dendritic spines, the tiny protrusions on neurons that are specialized for receiving information. These channels can open when they are exposed to cAMP (cyclic adenosine monophosphate). When open, the information can no longer flow into the cell, and thus the network is effectively disconnected. Arnsten said inhibiting cAMP closes the channels and allows the network to reconnect.
Guanfacine can strengthen the connectivity of these networks by keeping these channels closed, thus improving working memory and reducing distractibility," she said. "This is the first time we have observed the mechanism of action of a psychotropic medication in such depth, at the level of ion channels."
Arnsten said the excessive opening of HCN channels might underlie many lapses in higher cognitive function. Stress, for example, appears to flood PFC neurons with cAMP, which opens HCN channels, temporarily disconnects networks, and impairs higher cognitive abilities.
The study also found alpha-2A adrenergic receptors near the channels that inhibit the production of cAMP and allow the information to pass through into the cell, connecting the network. These receptors are stimulated by a natural brain chemical  norepinephrine or by medications like guanfacine.
 “Guanfacine can strengthen the connectivity of these networks by keeping these channels closed, thus improving working memory and reducing distractibility,” she said. “This is the first time we have observed the mechanism of action of a psychotropic medication in such depth, at the level of ion channels.”
Yale has submitted a patent application on the use of HCN blockers for the treatment of PFC cognitive deficits based on the data reported in the Cell paper.

The full Yale paper:

The prefrontal cortex (PFC) is among the most evolved brain regions, contributing to our highest order cognitive abilities. It regulates behavior, thought, and emotion using working memory. Many cognitive disorders involve impairments of the PFC. A century of discoveries at Yale Medical School has revealed the neurobiology of PFC cognitive functions, as well as the molecular needs of these circuits. This work has led to the identification of therapeutic targets to treat cognitive disorders. Recent research has found that the noradrenergic α2A agonist guanfacine can improve PFC function by strengthening PFC network connections via inhibition of cAMP-potassium channel signaling in postsynaptic spines. Guanfacine is now being used to treat a variety of PFC cognitive disorders, including Tourette’s Syndrome and Attention Deficit Hyperactivity Disorder (ADHD). This article reviews the history of Yale discoveries on the neurobiology of PFC working memory function and the identification of guanfacine for treating cognitive disorders.

Molecular modeling suggests that, similarly to ZD 7288, nicotine and epibatidine directly bind to the inner pore of the HCN channels. It is therefore likely that nicotine severely influences rhythmogenesis and high cognitive functions in smokers.

Modulation of HCN channels in lateral septum by nicotine


Conclusion
I think many people stand to benefit from the drugs mentioned in today’s post, but for different biological reasons. A person with Pitt Hopkins may benefit from Roflumilast because it will upregulate PKA and then increase expression of their remaining TCF4 gene.
In a person with schizophrenia there are multiple reasons these drugs might help them and it will depend on which genes they have that are misexpressed (TCF4, DISC1 etc.).
In a person with idiopathic Asperger’s and impaired sensory gating it looks like the effect on HCN channels is what is important.
I think low dose Roflumilast has great potential for many. The Japanese drug Ibudilast very likely will provide similar benefits, but at what dosage?
PDE4 inhibitors do have side effects at higher doses in part because there are several different types of PDE4 (PDE4A, PDE4B, PDE4C etc) and different drugs effect different subtypes differently.
Ibudilast is used as a daily drug therapy for asthma in Japan and is being studied as a therapy for Multiple Sclerosis (MS) in the US.
Roflumilast is sold by Astra Zeneca as Daxas/Daliresp but at a high dose of 500mcg to treat flare ups of COPD (Chronic Obstructive Pulmonary Disease) it does cause troubling side effects, but it reduces your chance of dying from COPD.
The cognitive dose used in research is 100mcg. Higher doses had no cognitive/sensory gating benefit.
Further investigation of the ADHD drug Guanfacine should be made, because some of the people who benefit from a PDE4 inhibitor might get a similar effect from Guanfacine. People with Pitt Hopkins would not be in this category. A person with Asperger’s and impaired sensory dating should respond to Guanfacine, a cheap drug.
At the end of the day, choice of therapy will come down to side effects and cost. In the US, Roflumilast is expensive ($330), seven times more expensive than in some other countries; in the UK the price of the same 30 tablets is $50. One pack would be enough for 5 months at the suggested dose.